The prevalence of obesity is rising. Even moderate obesity can contribute to the development of the pathological characteristics of the Metabolic Syndrome. Insulin resistance is the underlying characteristic of Metabolic Syndrome and, along with beta-cell dysfunction, results in Type 2 Diabetes Mellitus (T2DM). Due to the rising incidence of Metabolic Syndrome and T2DM and the limited ability of current treatments to prevent their long-term complications, it is clear that more attention needs to be focused on primary prevention of insulin resistance. In this application we propose to examine the long-term (1 year) effects of supplementation with fish oil and alpha lipoic acid; two widely used nutritional supplements known to activate PPARs and/or target lipid dysregulation, inflammation, and oxidative stress; to prevent or attenuate the progression of insulin resistance and dyslipidemia in a nonhuman primate model of the Metabolic Syndrome. The development of insulin resistance in obese rhesus monkeys shares similar features with the progression of metabolic disease in humans. We have previously demonstrated that providing obese rhesus monkeys with a sugar-sweetened beverage daily in combination with ad libitum access to their normal diet for 1 year results in modest weight and body fat gain accompanied by a rapid progression of insulin resistance and dyslipidemia (elevated triglyceride and reduced HDL levels). The use of this model in which rigorous control and compliance with diet and supplement intake can be ensured will allow us to determine the effects of long-term fish oil/lipoic acid supplementation in the progression of the Metabolic Syndrome. We will pursue the following specific aims: Specific Aim 1: We hypothesize that supplementation with fish oil will activate PPAR alpha, gamma and delta and prevent or attenuate the progression of insulin resistance. Specific Aim 2: We hypothesize that supplementation with alpha-lipoic acid will reduce oxidative stress and prevent or attenuate the progression of insulin resistance. Specific Aim 3: We will also investigate whether alpha-lipoic acid in combination with the fish oil PPAR activators (EPA & DHA) will be more effective than either fish oil or alpha- lipoic acid alone in preventing diabetes. In addition, we will assess the effects of the supplements on a number of lipid, oxidative stress and inflammatory parameters associated with insulin resistance and cardiovascular disease risk including substrate oxidation, apolipoprotein-B, lipoprotein particle size, adiponectin, C-reactive protein, homocysteine, interleukin-6, tumor necrosis factor-alpha, soluble adhesion factors, and PAI-1. [unreadable] [unreadable] [unreadable]